To the Editor: Margaret G. Woerner, Ph.D., and colleagues reported the interesting observation that clozapine, in comparison with fluphenazine, was similarly efficacious for new-onset patients with schizophrenia or schizoaffective disorder (1). These results were similar to a recent study by Lieberman et al., which they referenced. They also pointed out that these results stand in contrast to the comparisons between clozapine and typical antipsychotics in treatment-resistant patients, which have found that clozapine results in dramatically higher response rates.

Although the lack of an advantage for clozapine in new-onset patients may be disappointing, these studies raise an interesting question: why is clozapine, compared with typical antipsychotics, dramatically more efficacious for treatment-resistant psychosis but merely similarly efficacious for new-onset schizophrenia? We would like to propose an answer to this question.

It long has been thought that patients taking long-term neuroleptic medication experience upregulation of dopamine D₂ receptors in their brains. For example, dopaminergic upregulation in the nigrostriatal tracts is thought to underlie the pathophysiology of tardive dyskinesia, and there now is long-awaited human data to support this idea (2). Typical antipsychotics may cause the upregulation because they dissociate slowly from the D₂ receptor (3), and the neurons respond by trying to overcome the chronic blockade. In contrast, clozapine, which is a fast dissociator (3), may allow endogenous dopamine to activate the receptor enough to avoid the problem of upregulation.

In addition to dopaminergic upregulation in the nigrostriatal tracts, many investigators have suggested that dopaminergic upregulation may occur in mesolimbic or mesocortical tracts, leading to a worsening of psychosis beyond the original level. This phenomenon has been called "tardive psychosis" or "supersensitivity psychosis" (4). Because increasing the dose of the neuroleptic eventually will make the problem worse, tardive psychosis may be a major form of treatment-resistant psychosis. Although not proven, the concept of tardive psychosis may provide heuristic value for understanding the effects of antipsychotic medication.

Clozapine, in comparison with typical antipsychotics, may be more efficacious for treatment-resistant psychosis because it allows the reversal of the dopaminergic upregulation in the mesolimbic or mesocortical tracts, leading to an improvement in tardive psychosis.

On the other hand, clozapine, in comparison with typical antipsychotics, may not be more efficacious for new-onset schizophrenia because these patients have not been medicated previously and do not have dopaminergic upregulation that can be reversed.

Although this explanation may not be the whole story (for example, clozapine probably also has direct therapeutic effects through the D₂ or other receptors), it is a parsimonious interpretation of these data, and it suggests ideas that can be tested empirically.